JP2012513972A5

JP2012513972A5 -

Info

Publication number: JP2012513972A5
Application number: JP2011542858A
Authority: JP
Filing date: 2009-12-17
Publication date: 2014-10-02
Anticipated expiration: 2029-12-17

Description

・化合物８：4-ノル-3,5-セココレスト-6-エン-3-オール-5-オンオキシム、及び
・化合物９：7-ヒドロキシアミノ-4-ノル-3,5-セココレスト-6-アン-3-オール-5-オンオキシム；
195mg（0.502mモル）の４−ノル−３，５−セココレスト−６−エン−３−オール−５−オン（例1h−段階iiからの生成物）及び200mgのヒドロキシルアミン塩酸塩を、2mlのピリジンに添加する。その溶液を周囲温度で一晩、撹拌し、そして200mgのヒドロキシルアミン塩酸塩及び2mlのピリジンを添加する。反応媒体を周囲温度で一晩、再び撹拌し、次にそれを真空下で濃縮する。
残渣を水に取り、そして酢酸エチルにより３度、抽出する。有機相を組合し、NaClの飽和溶液により洗浄し、無水硫酸マグネシウム上で乾燥し、濾過し、そして真空下で濃縮する。 Compound 8 : 4-nor-3,5-secocholest-6-en-3-ol-5-one oxime , and Compound 9 : 7-hydroxyamino-4-nor-3,5-secocholest-6-an- 3-ol-5-one oxime ;
195 mg (0.502 mmol) of 4-nor-3,5-secocholest-6-en-3-ol-5-one (Example 1h—product from step ii) and 200 mg of hydroxylamine hydrochloride Add to pyridine. The solution is stirred overnight at ambient temperature and 200 mg hydroxylamine hydrochloride and 2 ml pyridine are added. The reaction medium is stirred again overnight at ambient temperature, then it is concentrated under vacuum.
The residue is taken up in water and extracted three times with ethyl acetate. The organic phases are combined, washed with a saturated solution of NaCl, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum.

Claims

Formula (I) below

[Where:
R ₁ is a hydrogen atom, or —CH ₃ , —CH ₂ —CN, —CH ₂ —OR ^a , —CH ₂ —SR ^a , —CH ₂ —SeR ^a , —C (O) OR ^a , —O — C (O) NR ^a R ^b , -C (O) NR ^a R ^b group, wherein (i) R ^a and R ^b are simultaneously or independently of each other a hydrogen atom or C ₁ -C ₆ Selected from alkyl, C ₃ -C ₆ cycloalkyl, aryl, heteroaryl groups, or (ii) R ^a and R ^b together with the nitrogen to which they are attached, a non-aromatic C ₃ -C ₆ heterocycle forming a, and the heterocyclic ring one or more double bonds, and / or one or more oxygen, it may have a sulfur or nitrogen atom,
R ₂ is a hydrogen atom, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl group, halogen atom, or the following formula (A):
R ^c -Q- (CH ₂ ) _n- (A)
Wherein (i) n represents an integer that can take any one of the values 1 to 8; and (ii) Q is an oxygen atom or a —NR ^a group (here And R ^a is as defined above, and R ^c is a hydrogen atom, or a C ₁ -C ₆ alkyl, aryl, heteroaryl group, heterocycle, C ₁ -C ₆ alkyl-C (O)-, aryl-C (O)-, heteroaryl-C (O)-, heterocycle-C (O)-, especially the following formula (C) or (D):

Or (iii) Q is a —OC (O) — group or a —NR ^a —C (O) — group, where R ^a is as defined above; And R ^c represents a hydrogen atom, or a C ₁ -C ₆ alkyl, aryl, heteroaryl group, heterocyclic ring,
R ₃ is a hydrogen atom, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, an aryl group, a heterocyclic ring, or a halogen atom, or -CN , -CF ₃ , -NO ₂ , -OR ^a , -SR ^a , -SO ₂ R ^a , -NR ^a R ^b , -OC (O) R ^a , -OC (O) NR ^a R ^b , -C ( O) represents OR ^a , —CONR ^a R ^b group, where R ^a and R ^b are as defined above;
R ₄ represents a hydrogen atom or a C ₁ -C ₆ alkyl group, or R ₃ and R ₄ together with the carbon atom to which they are attached form a (C ₃ -C ₆ ) -cycloalkyl group;
R ₅ represents a hydrogen atom or a C ₁ -C ₆ alkyl group, preferably a hydrogen atom or a hydroxyamino (—NH ₂ —OH) group; or
R ₄ and R ₅ together form an additional carbon-carbon bond, or a C ₃ -C ₆ cycloalkyl group, between the carbon atoms to which they are attached;
R ₆ is a hydrogen atom, or C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, aryl group, or -CN, -OR ^a , -SR ^a , —SO ₂ R ^a , —NR ^a R ^b , —OC (O) R ^a , —OC (O) NR ^a R ^b group (where R ^a and R ^b are as defined above), or Represents a hydroxyamino (—NH ₂ —OH) group;
R ₇ is a C ₄ -C ₁₂ alkyl group, a C ₄ -C ₁₂ alkenyl group, or a C ₄ -C ₁₂ alkynyl group, especially

A group selected from: and a compound represented by
-The SYN, ANTI isomer (if present),
-Its optical isomers (enantiomers, diastereomers) (if any),
-Addition salts thereof with pharmaceutically acceptable acids or bases,
-Hydrates and solvates thereof,
-The prodrug,
Except for the following compounds:
-Ester of 4-nor-3,5-secocholestan-5-one oxime-3-N, N-dimethylglycine;
-Ester hydrochloride of 4-nor-3,5-secocholestan-5-one oxime-3-N, N-dimethylglycine;
-4-nor-3,5-secocholestan-3-ol-5-one oxime;
-4-nor-3,5-secocholestane-3,5-dione dioxime;
-4-nor-3,5-secocholestan-5-one oxime-3- (4-methyl-1-piperazine) -propanoic acid ester;
-3-aminomethyl-4-nor-3,5-secocholestan-5-one oxime;
-4,5-secocholestan-3-ol-5-one oxime;
-3-methyl-4,5-secocholestan-3-ol-5-one oxime;
-3-N-methylcarboxamido-4-nor-3,5-secocholestan-5-one oxime;
-5-hydroxyimino-4-nor-3,5-secocholestane-3 -acid ;
-3,4-nor-2,5-secocholestan-5-one oxime;
-Methyl 5-hydroxyimino-4-nor-3,5-secostigumastan-3- acid ;
-Methyl 5-hydroxyimino-4-nor-3,5-secocholestane-3- acid ;
-4,5-secocholestane-3,5-dione dioxime;
-4,5-secocholestan-3-in-5-one oxime;
-24-Methyl-A-nor-1,5-secocholest-22-en-5-one oxime;
-3- (O-methyloxime) -4,5-secocholestane-3,5-dione 5-oxime;
-4-methylidyne-4,5-secocholestan-5-one oxime;
-4-methyl-4,5-secocholestan-3-in-5-one oxime;
-Methyl 5-hydroxyimino-4,5-secocholestan-4- acid ;
-5-hydroxyimino-4,5-secocholestan-4- acid ;
-3-oxo-4,5-secocholestan-5-one oxime;
-3-acetyloxy-4-nor-3,5-secocholestan-5-one oxime;
-4,5-secocholestan-4-ol-5-one oxime;
-3-hydroxymethyl-4,5-secocholestan-4-ol-5-one oxime;
-24-N, N-diethylcarbamoyl-3,5-seco-4-norcolan-5-hydroxyimino-3- acid .

R2 is represented by the formula (A):
R ^C -Q- (CH ₂ ) n- (A)
, Where n = 3,
Q represents a —NCH ₃ group, and
R ^C is the formula (C) or (D):

The compound of Claim 1 which represents group represented by these.

4-nor-3,5-seco-3- (trifluoromethyl) cholestan-3-ol-5-one oxime;
3-[(N-(+)-biotinoyl-N-methyl) amino] -4-nor-3,5-secocholestan-5-one oxime;
3- [methyl (7-nitro-2,1,3-benzoxadiazol-4-yl) amino] -4-nor-3,5-secocholestan-5-one oxime;
25-fluoro-4-nor-3,5-secocholestan-3-ol-5-one oxime;
4-nor-3,5-secocholestan-5-one oxime;
3,4-dinor-2,5-secocholestan-2-ol-5-one oxime;
4-nor-3,5-secocholest-24-en-3-ol-5-one oxime; or
24β-ethyl-4-nor-3,5-secocholest-22-en-3-ol-5-one oxime ,
The compound according to claim 1 or 2, wherein:

As a drug
3,4-nor-2,5-secocholestan-5-one oxime,
Methyl 5-hydroxyimino-4-nor-3,5-secostigumastan-3- acid ,
5-hydroxyimino-4-nor-3,5-secocholestane-3- acid methyl ,
4,5-secocholestan-3-in-5-one oxime,
24-methyl-A-nor-1,5-secocholest-22-en-5-one oxime,
4-methylidyne-4,5-secocholestan-5-one oxime,
4-methyl-4,5-secocholestan-3-in-5-one oxime,
5-hydroxyimino-4,5-secocholestane-4- acid methyl ,
3-acetyloxy-4-nor-3,5-secocholestan-5-one oxime, and / or
24-N, N-diethylcarbamoyl-3,5-seco-4-norcolan-5-hydroxyimino-3-acid,
A compound of formula I according to any one of claims 1 to 3 , comprising

For the preparation of cytoprotective drugs,
3,4-nor-2,5-secocholestan-5-one oxime,
Methyl 5-hydroxyimino-4-nor-3,5-secostigumastan-3- acid ,
5-hydroxyimino-4-nor-3,5-secocholestane-3- acid methyl ,
4,5-secocholestan-3-in-5-one oxime,
24-methyl-A-nor-1,5-secocholest-22-en-5-one oxime,
4-methylidyne-4,5-secocholestan-5-one oxime,
4-methyl-4,5-secocholestan-3-in-5-one oxime,
5-hydroxyimino-4,5-secocholestane-4- acid methyl ,
3-acetyloxy-4-nor-3,5-secocholestan-5-one oxime, and / or
24-N, N-diethylcarbamoyl-3,5-seco-4-norcolan-5-hydroxyimino-3- acid ,
Use of a compound according to any one of claims 1 to 4 comprising

Use according to claim 5 for the preparation of a cardioprotective and / or neuroprotective and / or hepatoprotective drug.

For the preparation of drugs intended for the treatment or prevention of necrosis and / or pathological apoptosis and / or necroptosis, or cells, in particular heart cells and / or neurons (the latter being natural or accidental For the preparation of drugs intended for the treatment of pathology or trauma related to
3,4-nor-2,5-secocholestan-5-one oxime,
Methyl 5-hydroxyimino-4-nor-3,5-secostigumastan-3- acid ,
5-hydroxyimino-4-nor-3,5-secocholestane-3- acid methyl ,
4,5-secocholestan-3-in-5-one oxime,
24-methyl-A-nor-1,5-secocholest-22-en-5-one oxime,
4-methylidyne-4,5-secocholestan-5-one oxime,
4-methyl-4,5-secocholestan-3-in-5-one oxime,
5-hydroxyimino-4,5-secocholestane-4- acid methyl ,
3-acetyloxy-4-nor-3,5-secocholestan-5-one oxime, and / or
24-N, N-diethylcarbamoyl-3,5-seco-4-norcolan-5-hydroxyimino-3- acid ,
Use of a compound according to any one of claims 1 to 4 comprising

The following obstacles, for example:
Diseases of bones, joints, connective tissue and cartilage;
Muscular diseases such as muscular dystrophy;
Skin disease;
Cardiovascular disease;
Cardiovascular disease;
Hematology and vascular disease;
Pulmonary diseases such as chronic obstructive pulmonary disease;
Gastrointestinal tract disease;
Liver disease;
Pancreatic disease;
Metabolic disease;
Kidney disease;
Viruses and bacterial infections;
Severe poisoning;
Degenerative diseases associated with acquired immune deficiency syndrome (AIDS);
Diseases associated with aging ;
Inflammatory diseases;
Autoimmune disease;
Dental disease;
Ophthalmic diseases or disorders;
Auditory canal disorders;
Mitochondrial disease;
-Neurological and neurodegenerative diseases;
For the preparation of drugs intended for the treatment of
3,4-nor-2,5-secocholestan-5-one oxime,
Methyl 5-hydroxyimino-4-nor-3,5-secostigumastan-3- acid ,
5-hydroxyimino-4-nor-3,5-secocholestane-3- acid methyl ,
4,5-secocholestan-3-in-5-one oxime,
24-methyl-A-nor-1,5-secocholest-22-en-5-one oxime,
4-methylidyne-4,5-secocholestan-5-one oxime,
4-methyl-4,5-secocholestan-3-in-5-one oxime,
5-hydroxyimino-4,5-secocholestane-4- acid methyl ,
3-acetyloxy-4-nor-3,5-secocholestan-5-one oxime, and / or
24-N, N-diethylcarbamoyl-3,5-seco-4-norcolan-5-hydroxyimino-3- acid ,
Use of a compound according to any one of claims 1 to 4 or an ester thereof and / or an addition salt thereof with a pharmaceutically acceptable acid.

The neuroprotective agent is Huntington's disease, hereditary or sporadic chronic neurodegenerative disease, age- related neuronal trauma, hereditary or trauma-induced peripheral neuropathy, Charcot-Marie- Tooth disease, anticancer treatment Diabetic neuropathy or neuropathy induced by, sputum, chronic demyelinating, and neurodegenerative diseases, especially multiple sclerosis and leukodystrophy, brain, peripheral nerve or spinal cord injury, brain or spinal cord ischemia, Hereditary, traumatic, or age- related degeneration of visual neurons, or optic nerve degeneration, inheritance of sensory neurons of hearing, traumatic or aging-related degeneration, lobe atrophy and vascular dementia, motor neuron From degenerative-related diseases and trauma, spinal muscular atrophy, especially infantile spinal muscular atrophy, multiple sclerosis, amyotrophic lateral sclerosis, and spinal cord or peripheral motor nerve damage Use according to claim 8, characterized in that it is intended for processing-option neural degenerative diseases.

Any neuroprotective agent, according to claim 5-9, wherein multiple sclerosis or spinal muscular atrophy, particularly infantile spinal muscular atrophy, or amyotrophic lateral sclerosis, that is intended for the treatment of Or use according to claim 1.

Use of a compound according to claim 2 as a tracer or label.

3,4-nor-2,5-secocholestan-5-one oxime,
Methyl 5-hydroxyimino-4-nor-3,5-secostigumastan-3- acid ,
5-hydroxyimino-4-nor-3,5-secocholestane-3- acid methyl ,
4,5-secocholestan-3-in-5-one oxime,
24-methyl-A-nor-1,5-secocholest-22-en-5-one oxime,
4-methylidyne-4,5-secocholestan-5-one oxime,
4-methyl-4,5-secocholestan-3-in-5-one oxime,
5-hydroxyimino-4,5-secocholestane-4- acid methyl ,
3-acetyloxy-4-nor-3,5-secocholestan-5-one oxime, and / or
24-N, N-diethylcarbamoyl-3,5-seco-4-norcolan-5-hydroxyimino-3-0 acid ,
A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 4 as an active ingredient and a pharmaceutically acceptable excipient.